October 15, 1996
February 1, 2007
(r) Registered Trade-mark Solvay Pharmaceuticals B.V., Licensed use by Solvay Pharma Inc. Markham ON L3R OC9
Anti-vertigo Agent
Betahistine is a histamine H1-agonist with an intrinsic activity equal to that of histamine and an H1-agonistic activity of about 0.07 times that of histamine. This H1-agonist activity has been confirmed in in vivo studies where, like histamine, the hypotensive response produced by betahistine could be blocked by H1-receptor antagonists.6,7,8 Betahistine also induces bronchoconstriction and increased vasopermeability after parenteral administration, further confirming its H1-agonistic properties.3,6,8 In contrast to histamine, betahistine is virtually inactive at the H2-receptor. Only marginal increases in gastric acid secretion are produced following very high parenteral doses of betahistine.11,12 The compound did not produce relaxation in the rat uterus,6 and no H2-agonist activity was noted in heart muscle.3 Receptor binding studies have shown that betahistine is a potent H3-receptor antagonist.22,23 Orally administered doses of betahistine dihydrochloride are rapidly and completely absorbed from the gastrointestinal tract. The drug is rapidly metabolized to one primary metabolite - 2- pyridylacetic acid and excreted in the urine. Studies with radio-labelled betahistine have demonstrated a plasma half life of 3.4 hours and a urinary half life of 3.5 hours for the radio- label. Urinary excretion of the label was about 90% complete within 24 hours of administration.16
,20
SERC (betahistine dihydrochloride) tablets are indicated for reducing the episodes of recurrent vertigo associated with Meniere's disease.
The use of SERC (betahistine dihydrochloride) tablets is contraindicated in patients with known hypersensitivity to betahistine or to any of the tablet constituents. Several patients with a history of peptic ulcer have experienced an exacerbation of symptoms while using SERC. Although experiments in animals and in humans have shown that the gastrointestinal side effects associated with betahistine dihydrochloride are not related to gastric acid production, SERC is contraindicated in the presence of peptic ulcer and in patients with a history of this condition. SERC is also contraindicated in patients with pheochromocytoma.
Although clinical intolerance to SERC (betahistine dihydrochloride) tablets has not been demonstrated in patients with bronchial asthma, caution should be exercised when giving the product to asthmatic patients.
SERC is not recommended for use in children.
The safety of SERC in human pregnancy has not been established. Its use in pregnancy or lactation, or in women of child-bearing potential requires that the potential benefits be weighed against the possible risks. The preclinical programme for betahistine dihydrochloride included a reproduction study in two generations of rats. No adverse effects were noted in any of the parameters assessed in this study.
Skin and subcutaneous tissue disorders
The most common adverse reactions reported in association with the use of SERC (betahistine dihydrochloride) tablets are skin rashes of various types, urticaria, and pruritus.
Nervous system disorders
Patients have experienced headache.
Gastrointestinal disorders
In some cases mild gastric complaints (e.g. nausea) have been observed. These can normally be minimized or eliminated by taking the dose with meals or by lowering the dose.
Postmarketing:
Hypersensitivity reactions, e.g. anaphylaxis have been reported. In very rare cases cutaneous hypersensitivity reactions such as angioneurotic oedema have been reported. There have been anecdotal spontaneous reports of somnolence and ventricular extrasystoles; although these events occurred during treatment with betahistine dihydrochloride the causal relationship has not been established.
A few overdose cases (up to 640 mg), with mild to moderate symptoms of nausea, dry mouth, dyspepsia and somnolence have been reported. At a dose of 728 mg a convulsion was reported. In all cases recovery was complete. Standard overdose protocol should be followed.
The usual daily dosage range is 24-48 mg administered orally in divided doses.
BID Dosing:
24 mg tablets: 1 tablet twice daily.
TID Dosing:
16 mg tablets: 1/2 to 1 tablet three times daily. As SERC (betahistine dihydrochloride) can cause gastrointestinal upset in some patients, it is recommended that doses be taken with a meal.
Proper Name:
Betahistine dihydrochloride
Chemical Name: 2-[2-(methylamino)ethyl]pyridine dihydrochloride Structural Formula: Molecular Weight: 209.1 Molecular Formula: C8H12N2.2HCl
Description:
Betahistine dihydrochloride is a white to almost white crystalline product which is very hygroscopic. The product is very soluble in water, freely soluble in methanol and 96% methanol, and slightly soluble in isopropanol. The pKa values are 3.5 and 9.7. The substance melts at about 152 degC.
:
The 16 mg and 24 mg tablets contain 16 mg and 24 mg of betahistine dihydrochloride respectively. Non-medicinal ingredients include: citric acid, colloidal anhydrous silica, mannitol, microcrystalline cellulose, and talc.
Store tablets at controlled room temperature (15-30degC) and protect from exposure to moisture.
SERC (betahistine dihydrochloride) tablets are available as follows: 16 mg tablets: Round, biconvex, scored, white to almost white tablet with bevelled edges, one side inscribed with " " , the other side with "267" on either side of the score. The diameter of the tablet is 8.5 mm. The tablets are individually blister packaged and are provided in boxes of 100. 24 mg tablets: Round, biconvex, scored, white to almost white tablet with bevelled edges, one side inscribed with " ", the other side with "289" on either side of the score. The diameter of the tablet is 10 mm. The tablets are individually blister packaged and are provided in boxes of 100.
This (booklet/leaflet/sheet) contains general information about SERC. If you need more specific information, ask your doctor or pharmacist. It is important for you to carefully follow your doctor's instructions regarding how and when to take SERC.
SERC is the brand name for a drug called "betahistine dihydrochloride". SERC is used for reducing the episodes of recurrent vertigo associated with Meniere's disease.
There are a few things your doctor should know about your health before you take SERC. This will help your doctor decide if SERC is the best medicine for you at this time. Be sure to tell your doctor:
if you have a peptic ulcer or have a history of this condition;
if you have pheochromocytoma;
about all health problems you have now, or have had in the past;
about all other medications you take, including ones you can take without a doctor's prescription including, for example, "natural" or "herbal" remedies;
if you are pregnant, plan to become pregnant, or are breastfeeding;
if you are allergic to any of the components that are present in SERC tablets (see "What is in SERC").
It is very important to take SERC exactly as your doctor has instructed. If you're not sure when or how many tablets to take each day, check with your doctor or pharmacist. SERC is not recommended for use in children. It is recommended that SERC tablets be taken with meals. If you forget to take one dose of SERC, take a tablet (s) as soon as you remember, unless it is almost time for your next dose. If it is almost time for your next dose, do not take the missed tablet (s) at all. Never double-up on a dose to make up for the one you have missed; just go back to your regular schedule.
Like any medication, SERC may cause side effects in some people. Most people have few or no side effects from SERC. Side effects that do occur tend to be generally mild and do not last a long time. The few side effects that have been reported are skin rashes of various types, hives, itching, stomach-ache, nausea and headache. If any of these become troublesome, consult your doctor. If in the rare event you experience a severe allergic reaction (which might include but is not limited to breathing or swallowing difficulties, or swelling in the face or skin) consult your doctor immediately. If you experience any unusual or unexpected symptoms while using SERC consult your doctor.
If you or someone you know takes a lot more than the recommended dose (an overdose) you should immediately contact either your doctor, pharmacist, hospital emergency department or nearest Poison control centre, even if you do not feel sick.
Each SERC 16 mg and 24 mg tablet contains either 16 mg or 24 mg of betahistine dihydrochloride, respectively, and the following non-medicinal ingredients: citric acid, colloidal anhydrous silica, mannitol, microcrystalline cellulose, and talc. Check with your doctor whether you might be allergic to any of the above ingredients.
The 16 mg tablets are round, biconvex, scored, white to almost white tablet with bevelled edges, one side inscribed with " " , the other side with "267" on either side of the score. The 24 mg tablets are round, biconvex, scored, white to almost white tablet with bevelled edges, one side inscribed with " " the other side with "289" on either side of the score.
Keep your tablets at room temperature (15 to 30degC), protect from exposure to moisture, and where children cannot reach them.
This information is intended to alert you to some of the times when you should call your doctor or pharmacist. Other situations which cannot be predicted may arise while you are taking medicines. Nothing should stop you from calling your doctor or pharmacist with any questions or concerns you have about using SERC.
(r) Registered Trade-mark Solvay Pharmaceuticals B.V., Licensed use by Solvay Pharma Inc. Markham ON L3R OC9
Animal: Pharmacodynamics In vitro:
In studies on a variety of isolated organs and isolated tissues, betahistine dihydrochloride produced responses similar to those induced by histamine. Betahistine had little or no affinity for histamine H2-receptors as confirmed by its activity in tests using rat uterine muscle,6 rabbit and guinea pig hearts and atrial pairs,3 and isolated guinea pig ileum.6
In vivo:
In evaluations of its effects on the circulation of the inner ear, betahistine dihydrochloride was found to produce greater effects than histamine. Betahistine increased blood flow in the labyrinthine arteries of dogs by 60.9% following a dose of 100 ug.1 Circulation in the stria vascularis and spiral ligament of guinea pigs and chinchillas was increased by a mean of 50% when betahistine was administered at doses as low as 0.1 mg/animal.2 In guinea pigs, cochlear blood flow was increased for 30 minutes following a dose of 0.2 mg/kg.3,4,5 Studies of the effects on the cardiovascular system, the pulmonary system, the renal system, the gastrointestinal system, and the central nervous system all indicated that betahistine produced effects similar to, but less potent than, those of histamine. Following rapid intravenous administration of betahistine dihydrochloride, a brief fall in blood pressure was evoked in rats, guinea pigs, dogs, and cats.6,7 This effect could be blocked by the administration of histamine H1-antagonists, but not by histamine H2-antagonists. When betahistine was injected slowly into anaesthetized dogs, general blood pressure decreased while basilar blood flow increased by up to 200%.8 Pronounced increases in blood flow were found in the coronary (225%), labyrinthine (161%), and communicating hepatic arteries (156%). Intravenous doses of 0.2 to 0.4 mg/kg given to anaesthetized guinea pigs produced an increase in pulmonary resistance.3 Administration of an intraperitoneal doses of 40 mg/kg caused death by respiratory failure.6 In the perfused baboon kidney, the addition of betahistine to the perfusate produced increases in urine flow, osmotic clearance, urea and creatinine clearance.10 Betahistine doses of 80 to 1600 ug/kg/min administered as a continuous infusion to dogs with Heidenhain pouches produced a slight increase in the rate of acid secretion corresponding to 8.8% to 17.6% of the maximum response to histamine.11 In dogs with gastric fistulae, an increase in acid secretion was obtained with a subcutaneous dose of 20 mg/kg betahistine. This increase corresponded with that produced by 30 ug/kg of histamine.12 The effect of betahistine on continuous avoidance behaviour in rats was compared with that of histamine.13 Betahistine injected intraventricularly at a dose of 0.32 mg/animal and histamine at a dose of 0.08 mg/animal produced a significant increase in the avoidance rate; an increase was also observed after an intraperitoneal dose of 4.0 mg/kg betahistine, but this did not achieve statistical significance.13 Betahistine did not affect the righting reflex when given to newborn chicks at a dose of 100 mg/kg, while a dose of 50 mg/kg histamine produced sleep characterized by loss of the righting reflex.14
Pharmacokinetics
The absorption, distribution, metabolism, and excretion of betahistine dihydrochloride were studied in female rats.15,16,17 Following the oral or intravenous administration of 0.5 mg radio- labelled compound, total excretion of the radioactive label was 80 to 90%, about 67% of which was in the urine. Of the total excretion which took place, 98.5% appeared in the urine within 24 hours.15 The metabolite pattern in rat urine showed only one main metabolite - 2-pyridylacetic acid.16 The distribution of radio-labelled betahistine was evaluated at 0.5, 1, 3, 6, 24 or 48 hours after the oral or intravenous administration of a 1 mg dose.17 Following intravenous administration, radioactivity was distributed rapidly throughout the body, with immediate and intensive secretion into the stomach and intestines. There was a transient accumulation of radioactivity in the liver and the portal vein. After oral administration, radioactivity was distributed throughout the body, with high accumulation in the stomach and intestines. Levels of radioactivity in excess of blood levels were observed in the bronchial epithelium, the eye, and the preputial gland. At 24 hours, only the preputial gland and the alimentary system still showed evidence of accumulated radioactivity. By 48 hours, there was no remaining activity.
Human Studies:
Pharmacodynamics
In ten healthy male volunteers, single oral doses of 8, 16, and 32 mg of betahistine given in a placebo-controlled, double-blind cross-over study produced dose-related effects on the vestibular system, as measured by electronystagmography (ENG).18 Maximal effects on the slow nystagmus phase were found 3 to 4 hours after drug intake. Nystagmus duration was reduced by a mean value of 35% (after 8 mg), 48% (16 mg), or 59% (32 mg); all reductions were statistically significant (p<0.0005). Eleven patients with Meniere's disease were treated in a three month, open-label study of the pharmacological effects of betahistine on hearing and ENG-recorded, rotation-induced nystagmus.19 The study participants took one, 8 mg tablet three times a day (total daily dose, 24 mg). The speed of the quick phase of eye shift pre-treatment versus that achieved at the end of the three month treatment period was used as the parameter of effectiveness in this study. Hearing was evaluated pre- and post-treatment using three pure tone hearing levels (250, 500, 1000 Hz). Hearing loss was less after treatment but the difference did not achieve statistical significance. At some rates of acceleration and at all rates of deceleration, there was an increase in the mean eye shift per second; this increase reached statistical significance in six of the 12 tests.
Pharmacokinetics
The pharmacokinetic profile of betahistine was studied in six healthy male volunteers.20 Tablets containing 8 mg of radio-labelled betahistine were administered to the subjects following an overnight fast, 30 minutes before a standard breakfast. Urine was collected for at least 56 hours after dosing, and five blood samples were drawn from each volunteer at 1, 2, 3, 8, and 25 hours for the first two volunteers, and at 1, 2, 3, 5.5, and 8 hours for the next four subjects. Total urinary excretion of the radio-label was 90.7%, and the urinary half life was 3.5 hours. More than 85% of the administered dose was excreted in the urine within 24 hours. Only one primary urinary metabolite was identified - 2-pyridylacetic acid.16 Maximum plasma levels of radioactivity were attained by the 1 hour sampling time; the plasma half life of the radio-label was 3.4 hours.
Acute Toxicity:
The oral LD50 for betahistine dihydrochloride is 3040 mg/kg in the albino rat. The intravenous LD50 is 5.1 mg/kg in the rabbit. Signs of toxicity included ataxia, salivation, inactivity, hyperpnoea, tremors, and cyanosis. Severe gastroenteritis was noted during pathology.21
Chronic Toxicity:
In a six month study, dogs were given of up to 25 mg/kg/day. There were no significant abnormalities noted in any of the parameters assessed. In rats given doses of up to 120 mg/kg/day for 18 months, there were no significant abnormalities noted in any of the parameters assessed.21
Reproduction and Teratology:
A reproductive study which examined two generations of rats revealed no adverse effects on any of the parameters which were assessed.21
(r) Registered Trade-mark Solvay Pharmaceuticals B.V., Licensed use by Solvay Pharma Inc. Markham ON L3R OC9
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Martinez D.M. The effect of SERC (betahistine dihydrochloride) on the circulation of the inner ear in experimental animals. Acta Otolaryngol 1970; Suppl 305:29-47.
Snow J.B., Suga F. Labyrinthine vasodilators. Acta Otolaryngol 1973; 97:365-70.
Suga F., Snow J.B. Cochlear blood flow in response to vasodilating drugs and some related agents. Laryngoscope 1969; 79:1956-79.
Snow J.B., Suga F. Control of the microcirculation of the inner ear. Otol Clin North America 1975; 8:455-6.
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Smith K.A., Meyer M.W. Distribution of cardiac output in dogs during intravenous infusion of betahistine. Stroke 1976: 7(3):357-60.
Baez S. Antagonistic effects of histamine and betahistine on the vasoconstrictor actions of catecholamines in mesentery microvessels. Int Conference on Microcirculation, Gothenburg, Sweden. Bibl Anat 1969; 10:340-8.
Groenewald J.H., Retief C.P., Murphy G.P. The effects of betahistine on the isolated perfused baboon kidney. S Afr Med J 1970; 44:1002-5.
Curwain B.P., Holton P., Spencer J. The effect of betahistine on gastric acid secretion and mucosal blood flow in conscious dogs. Br J Pharmacol 1972; 46:351-4.
Van den Brink F.G. Histamine and antihistamines. Thesis, University of Nijmegen, 1969.
Gerald M.C., Maickel R.P. Studies on the possible role of brain histamine in behaviour. Br J Pharmacol 1973; 44:462-71.
Delbarre B., Schmitt H., Senon D. Effects of activation of H1- and H2-receptors on central cardiovascular structures in cats and on behaviour in chickens. Br J Pharmacol 1976; 58:443-44.
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Oosterveld W.J. Effect of betahistine dihydrochloride on induced vestibular nystagmus: a double blind study. Clin Otolaryngol 1987; 12:131-4.
Wilmot T.J. An objective study of the effect of betahistine dihydrochloride on hearing and vestibular function tests in patients with Meniere's disease. J Laryngol Otol 1971; 85:369-73.
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Arrang J., Garbarg M., Quach T.T., Tuong M.D., Yeramian E., Schwartz J. Actions of betahistine at histamine receptors in the brain. European Journal of Pharmacology 1985; 111:73-84.
Van Cauwenberge P.B. and De Moor S.E.G. Physiopathology of H3-receptors and pharmacology of betahistine. Acta Otolaryngol (Stockh) 1997; 526: 43-46. SELECTED BIBLIOGRAPHY
Frew I.J.C., Menon G.N. Betahistine hydrochloride in Meniere's disease. Postgrad Med J 1976; 52:501-503.
Wilmot T.J., Menon G.N. Betahistine in Meniere's disease. J Laryngol Otol 1976; 90:833-840.
Oosterveld W.J. Betahistine dihydrochloride in the treatment of vertigo of peripheral vestibular origin. A double-blind placebo-controlled study. J Laryngol Otol 1984; 98:37-41.
Burkin A. Betahistine treatment of Meniere's syndrome. Clin Med 1967; 74:41-48.
Bertrand R.A. Meniere's disease: Subjective and objective evaluation of medical treatment with betahistine HCl. Acta Otolaryngol Suppl 1970; 305:48-69.